At UNHCR, Vieira de Mello participated in field work assignments in Bangladesh during its war of independence in 1971, in Sudan in 1972 following the Addis Ababa agreement which ended the First Sudanese Civil War and allowed the return of some 650,000 Sudanese refugees and displaced persons,[8] and Cyprus after the Turkish invasion in 1974.[9] These early assignments were operational, rather than political: he was helping to organize food aid, shelter and other types of aid to refugees. He continued field assignments with a posting in Mozambique to help refugees fleeing white supremacist rule and civil war in Zimbabwe (at the time, still Rhodesia) where he was deputy head of the office but due to absence of his boss was effectively running the mission.[10] In 1973, he married Annie, a French assistant at UNHCR, with whom he had two sons, Laurent and Adrien.[citation needed] During his early years at UNHCR, he also completed an MA in moral philosophy and a PhD by correspondence from the Sorbonne.[11] His doctorate thesis, submitted in 1974, was entitled The Role of Philosophy in Contemporary Society.[12] In 1985, he submitted a second "state" doctorate, the highest degree in the French education system, entitled Civitas Maxima: Origins, Foundations and Philosophical and Political Significance of the Supranationality Concept.[13] In addition to his native Portuguese, Vieira de Mello was fluent in English, Spanish, Italian and French, as well as some conversational Arabic and Tetum.

Vieira de Mello spent three years in charge of UNHCR operations in Mozambique during the civil war that followed its independence from Portugal in 1975, and three more in Peru. Vieira de Mello also served as Special Envoy for the United Nations High Commissioner for Refugees for Cambodia, being the first and only UN Representative to hold talks with the Khmer Rouge. He became senior political adviser to the UN Interim Force in Lebanon between 1981 and 1983.

In May 2003 Vieira de Mello was appointed as the Special Representative of the UN Secretary General to Iraq, an appointment initially intended to last for four months. According to The New York Times Magazine journalist James Traub in his book The Best Intentions, Vieira de Mello had originally turned down the appointment before being persuaded by US President George W. Bush and Condoleezza Rice. According to Samantha Power in her book Sergio: One Man's Fight to Save the World, Vieira de Mello had charmed Bush at a meeting in March 2003, at which the two men discussed the human rights situation in the Guantanamo Bay detention camp, a controversial issue for the United States. Power reports that Vieira de Mello bonded with Bush by telling him that he had authorized military force to combat terrorism while working as UN Transitional Administrator in East Timor.[16]

Vieira de Mello was working as Special Representative of the UN Secretary General to Iraq when he was killed in the Canal Hotel bombing. Abu Musab Zarqawi, a leader of the al-Qaeda terrorist organization, claimed responsibility for the blast.[17] A communiqué from al-Qaida said that de Mello was assassinated because he was a crusader that extracted a part of the Islamic land (East Timor) after the Indonesian regime committed genocide on the small country with Christian majority.[18]

He had been mentioned in some circles as a suitable candidate for UN Secretary-General.[19] His death was widely mourned, largely on account of his reputation for effective work to promote peace. Vieira de Mello was buried at the Cimetière des Rois in Geneva, Switzerland.

On 11 December 2008, the United Nations General Assembly made history when it adopted Swedish-sponsored GA Resolution A/63/L.49 on the Strengthening of the Coordination of Emergency Assistance of the United Nations,[21] that amongst other important humanitarian decisions, decided to designate 19 August as the World Humanitarian Day (WHD). The Resolution gives for the first time, a special recognition to all humanitarian and United Nations and associated personnel who have worked in the promotion of the humanitarian cause and those who have lost their lives in the cause of duty and urges all Member States, entities of the United Nations within existing resources, as well as the other International Organizations and Non-Governmental Organizations to observe it annually in an appropriate way. As a background to this landmark resolution, the family of Sérgio Vieira de Mello resolved to work towards having 19 August recognized as a befitting tribute to all humanitarian personnel. Early April 2008 the Board of the Sérgio Vieira de Mello Foundation prepared a draft Resolution to be sponsored and adopted by the General Assembly designating 19 August as World Humanitarian Day. France, Switzerland, Japan and Brazil, contacted with the draft Resolution, agreed to co-sponsor it.